Trichloroisocyanuric acid (TICA) in H2SO4 is an efficient reagent for regioselective chlorination of isatin at the 5-position and deactivated aromatic compounds, such as nitrobenzene. DFT calculations suggest formation of a superelectrophilic polyprotonated species that can transfer Cl+ to the aromatic ring more efficiently than TICA due to charge-charge repulsion relief.

Isatin (1H-indole-2,3-dione) is a versatile molecule with important applications in synthetic organic chemistry.1 Some of its derivatives, specifically 5-haloisatins, show a wide range of biological and pharmacological activity, such as antibacterial, antifungal, and anti-HIV, to name a few.2 They can be prepared by the laborious Sandmeyer and similar methodologies from p-haloanilines or by direct halogenation of isatin.1,3 Several reagents that perform the chlorination of isatin mainly in the 5-position are described in the literature. Among them, we can find N-chloroamides and N-chloroimides3 and recently we reported the regiospecific preparation of 5-chloroisatin in 48% yield using N-chlorosaccharin in a heterogeneous media (SiO2 / CH2Cl2).4

The chlorination of aromatic compounds is well-documented in the literature. However, direct chlorination of deactivated aromatic compounds is frequently disappointing. An efficient electrophilic chlorination of deactivated aromatic compounds with NCS / BF3 / H2O was recently published.5

Trichloroisocyanuric acid (TICA) has proven to be a mild oxidant6 and an efficient reagent for performing the cohalogenation of alkenes under mild conditions, thus serving as a new source of electrophilic chlorine to prepare chlorohydrins, b-chloroethers and b-chloroacetates.7 This reagent is a stable and inexpensive solid frequently found in a large number of commercial products for swimming-pool disinfection and easily available in pool supply and some hardware stores.8

Continuing7,9 our desire to use TICA as a source of electrophilic chlorine, we now communicate our results on the chlorination of isatin and other aromatic compounds.

Results and Discussion

The results of the reaction of isatin with trichloroisocyanuric acid to produce 5-chloroisatin are summarized in Table 1. Using CH2Cl2 as solvent, the reaction was incomplete after 72 h at rt and the product was obtained in less than 2 % yield. Even with the utilization of an excess of TICA and SiO2 as catalyst, 5-chloroisatin was isolated in only 29 % yield after 98 hours. However, the chlorination of isatin was efficiently achieved using just 0.34 mol equivalent of TICA in the presence of H2SO4 to give the desired product in 72 % of isolated yield in less than 5 minutes. No N-chlorination of isatin10 nor significant amount of the frequently formed isomeric 7-chloroisatin3 was detected in the crude reaction product by coinjection in HRGC (high-resolution gas chromatography) with authentic 7-chloroisatin.

We believe that the strongly acid media promotes the formation of a superelectrophilic species11 (e.g. Figure 1), where TICA being either polyprotonated or protosolvated,12 causing the "Cl+" transfer to isatin more efficiently due to the charge-charge repulsion relief.

Density functional theory (DFT) calculations on TICA and its mono-, di- and triprotonated species13 (Figure 2) could estimate their ability to release Cl+, which would be correlated with its reactivity as an electrophile. Table 2 shows the heats of reaction for loss of Cl+ from TICA and its protonated forms. As one can see, the increase of the degree of protonation of TICA leads to a more reactive intermediate that can release Cl+ to a nucleophile (e.g. the p system of an aromatic ring) more easily. This can be understood if one considers that the release of the Cl+ in a highly protonated form of TICA leads to a decrease in charge-charge (coulombic) repulsion into the molecule, thus decreasing its energy. Hence the highly protonated species works as a very powerful electrophile, whose reactivity can be regulated by the acid strength of the medium. As expected, bond lengths between N-Cl in the protonated species (Figure 2) increase when going from the unprotonated species (1.705 Å) to the triprotonated species (1.734 Å), which reflect these intramolecular coulombic repulsions. Actually, monoprotonation of TICA in H2SO4 is exothermic by 12.0 kcal mol-1. On the other hand, di- and triprotonation are endothermic respectively by 77.6 kcal mol-1 and 235.9 kcal mol-1 (see Supplementary Information). Thus, probably there is a higher concentration of monoprotonated species in this media. However, the de facto reacting species could either be any of the polyprotonated species, with the species with higher protonation degree having a stronger electrophilic character, thus being able to chlorinate weaker p nucleophiles.

Based on the relative energies for the s-complexes involved on the chlorination of isatin at B3LYP/6-31++G** level, chlorination should take place preferentially at the 5-position, followed by the product at the 7-position, which is 4.4 kcal mol-1 less stable than the former. Attacks in other positions afford intermediates that are about 20 kcal mol-1 higher in energy (see Supplementary Information), thus not being favorable from the energetic point of view.

In order to test this hypothesis we used both TICA and TICA / H2SO4 in the chlorination of aromatic rings of different reactivity (Table 3). Anisole gave o- and p-chloroanisole (91%) in 1.5 h by the reaction with 0.34 mol equiv. TICA. However, the same reaction performed in the presence of H2SO4 produced mainly 2,4,6-trichloroanisole (28%) in only 5 min. Reaction of TICA with toluene produced o- and p-chlorotoluene (50% yield, incomplete reaction after 5 days) and a mixture of several chlorinated products in 20 min in the case of reaction with TICA / H2SO4. Chlorobenzene gave no reaction at all with TICA while its reaction with TICA / H2SO4 produced a mixture of dichloro- and trichlorobenzenes. Nitrobenzene was only chlorinated with TICA / H2SO4 at 80 ºC after 5 h to produce m-chloro-nitrobenzene in 80 % yield. Our method is easier to execute than the reaction of nitrobenzene with NCS / BF3 / H2O in a closed pressure tube heated to 105-110 ºC over 18 h to give the same product in 69 % yield.5

The DFT calculations corroborate the above experimental results which show that increasing the acidity of the media led to higher yields in shorter reaction times, even for non reactive substrates, such as chlorobenzene and nitrobenzene.

Conclusions

In summary, we have developed a very attractive and simple methodology for the regiospecific preparation of 5-chloroisatin in 72 % yield, in 5 min and using just 0.34 mol equiv. of trichloroisocyanuric acid.14 The reaction conditions employed and the isolated yield obtained seem to be considerably better than those reported in the literature.3 Furthermore, our methodology permits the chlorination of deactivated substrates, such as nitrobenzene in high yield.

Acknowledgements

We thank W. Bruce Kover (IQ/UFRJ) for helpful discussions and Flavio A. Violante (IQ/UFRJ) for the authentic samples of chloroisatins. GFM thanks PIBIC/UFRJ for a fellowship. PME acknowledge to CNPq (PROFIX) and FAPERJ for financial support.

Supplementary Information

Tables containing the relative enthalpies (298K, 1 atm) of the protonation of TICA by H2SO4 (Table S1) and the s-complexes involved in the chlorination of isatin (Table S2) are available free of charge as PDF file at http://jbcs.sbq.org.br.